Sónia do Vale

The Relationship between Dehydroepiandrosterone (DHEA), Working Memory and Distraction – A Behavioral and Electrophysiological Approach

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulphate (DHEAS) have been reported to have memory enhancement effects in humans. A neuro-stimulatory action and an anti-cortisol mechanism of action may contribute to that relation. In order to study DHEA, DHEAS and cortisol relations to working memory and distraction, we recorded the electroencephalogram of 23 young women performing a discrimination (no working memory load) or 1-back (working memory load) task in an audio-visual oddball paradigm. We measured salivary DHEA, DHEAS and cortisol both before each task and at 30 and 60 min. Under working memory load, a higher baseline cortisol/DHEA ratio was related to higher distraction as indexed by an enhanced novelty P3. This suggests that cortisol may lead to increased distraction whereas DHEA may hinder distraction by leading to less processing of the distractor. An increased DHEA production with consecutive cognitive tasks was found and higher DHEA responses attributed to working memory load were related to enhanced working memory processing as indexed by an enhanced visual P300. Overall, the results suggest that in women DHEA may oppose cortisol effects reducing distraction and that a higher DHEA response may enhance working memory at the electrophysiological level.

Molecular characterization of parathyroid tumors from two patients with hereditary colorectal cancer syndromes

The tumor suppressor adenomatous polyposis coli (APC) has recently been implicated in parathyroid development. We here report clinical, histopathological and molecular investigations in parathyroid tumors arising in two patients; one familial adenomatous polyposis (FAP) syndrome patient carrying a constitutional APC mutation, and one Lynch syndrome patient demonstrating a germline MLH1 mutation as well as a non-classified, missense alteration of the APC gene. We sequenced the entire APC gene in tumor and constitutional DNA from both cases, assessed the levels of APC promoter 1A and 1B methylation by bisulfite Pyrosequencing analysis and performed immunohistochemistry for APC and parafibromin. In addition, copy number analysis regarding the APC gene on chromosome 5q21-22 was performed using qRT-PCR. Histopathological workup confirmed both tumors as parathyroid adenomas without signs of malignancy or atypia. No somatic mutations or copy number changes for the APC gene were discovered in the tumors; however, in both cases, the APC promoter 1A was hypermethylated while the APC promoter 1B was unmethylated. APC promoter 1B-specific mRNA and total APC mRNA levels were higher than in normal parathyroid samples. Immunohistochemical analyses revealed strong APC protein immunoreactivity and positive parafibromin expression in both parathyroid tumors. Absence of additional somatic APC mutations and copy number changes in addition to the positive APC immunoreactivity obtained suggest that the tumors arose without biallelic inactivation of the APC tumor suppressor gene. The finding of an unmethylated APC promoter 1B and high APC 1B mRNA levels could explain the maintained APC protein expression. Moreover, the findings of positive parafibromin and APC immunoreactivity as well as a low MIB-1 proliferation index and absence of histopathological features of malignancy/atypical adenoma indicate that the parathyroid adenomas arising in these patients did not harbor malignant potential.

Rare and severe complications of congenital adrenal hyperplasia due to 21-hydroxylase deficiency: a case report

IntroductionWe report the case of a patient with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency who presented with unusual anatomical and biochemical features, namely massively enlarged adrenal glands, adrenogenital rest tissue and an unexpected endocrine profile. The contribution of the adrenocortical cells in the adrenals and testicles was determined by a cosyntropin stimulation test before and after adrenalectomy. To the best of our knowledge this is the first report of such a case in the literature.Case presentationA 35-year-old Caucasian man was admitted to the emergency room with an Addisonian crisis. He had been diagnosed with congenital adrenal hyperplasia in the neonatal period. He acknowledged poor adherence to treatment and irregular medical assistance. Physical examination revealed marked cutaneous and gingival hyperpigmentation, hypotension, and hard nodules in the upper pole of both testicles. Blood analysis showed mild anemia and hyponatremia and no evidence of acute infection. Endocrine evaluation showed very low cortisol levels, low dehydroepiandrosterone-sulfate and elevated corticotropin, 11-deoxycortisol and delta-4-androstenedione. The concentration of 17-hydroxyprogesterone was 20,400ng/dL. After the cosyntropin stimulation test the pattern was similar and there was no significant increase in cortisol or 17-hydroxyprogesterone. The abdominal computed tomography scan revealed grossly enlarged and heterogeneous adrenal glands (left, 12cm; and right, six cm). A bilateral adrenalectomy was performed and pathologic examination revealed adrenal myelolipomas with nodular cortical hyperplasia. The sonogram showed bilateral heterogeneous masses on the upper pole of both testes which corresponded to the nodular hyperplasia of adrenal rest tissues. The genetic study revealed compound heterozigoty (mutations R124H and R356W), suggestive of a phenotypically moderate disease. We performed a cosyntropin stimulation test after adrenalectomy. The steroidogenic profile displayed the same unusual features, indicating an important contribution from the adrenogenital cells.ConclusionThis case illustrates that congenital adrenal hyperplasia due to 21-hydroxylase deficiency can progress to severe acute and chronic complications. The masses in the patient’s adrenal glands and testicles resulted from chronically elevated adrenocorticotropic hormone and growth of adrenocortical cells. The basal and stimulated steroid profile, before and after adrenalectomy, revealed an unexpected pattern, suggesting significant contribution of the testicular adrenal cells to the steroidogenesis.

Mild Adrenal Steroidogenic Defects and ACTH-Dependent Aldosterone Secretion in High Blood Pressure: Preliminary Evidence

Introduction. Adrenal glands play a major role in the control of blood pressure and mild defects of steroidogenesis and/or inappropriate control of mineralocorticoid production have been reported in high blood pressure (HBP). Patients and Methods. We used a specific protocol for the evaluation of 100 consecutive patients with inappropriate or recent onset HBP. Specific methods were used to confirm HBP and to diagnose secondary forms of HBP. In addition we tested adrenal steroidogenesis with the common cosyntropin test, modified to include the simultaneous measurement of renin and aldosterone besides 17-hydroxyprogesterone (17OHP) and 11-deoxycortisol (S). Results. Secondary forms of HBP were diagnosed in 32 patients, including 14 patients with primary hyperaldosteronism (PA) (14%) and 10 patients with pheochromocytoma (10%). Mild defects of the 21-hydroxylase (21OHD) and 11-hydroxylase (11OHD) enzymes were common (42%). ACTH-dependent aldosterone secretion was found in most patients (54%) and characteristically in those with mild defects of adrenal steroidogenesis (>60%), PA (>75%), and otherwise in patients with apparent essential HBP (EHBP) (32%). Discussion. Mild defects of adrenal steroidogenesis are common in patients with HBP, occurring in almost half of the patients. In those patients as well as in patients with apparent EHBP, aldosterone secretion is commonly dependent on ACTH.

Hormonal modulation of novelty processing in women: Enhanced under working memory load with high dehydroepiandrosterone-sulfate-to-dehydroepiandrosterone ratios

Several studies have suggested that dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEAS) may enhance working memory and attention, yet current evidence is still inconclusive. The balance between both forms of the hormone might be crucial regarding the effects that DHEA and DHEAS exert on the central nervous system. To test the hypothesis that higher DHEAS-to-DHEA ratios might enhance working memory and/or involuntary attention, we studied the DHEAS-to-DHEA ratio in relation to involuntary attention and working memory processing by recording the electroencephalogram of 22 young women while performing a working memory load task and a task without working memory load in an audio-visual oddball paradigm. DHEA and DHEAS were measured in saliva before each task. We found that a higher DHEAS-to-DHEA ratio was related to enhanced auditory novelty-P3 amplitudes during performance of the working memory task, indicating an increased processing of the distracter, while on the other hand there was no difference in the processing of the visual target. These results suggest that the balance between DHEAS and DHEA levels modulates involuntary attention during the performance of a task with cognitive load without interfering with the processing of the task-relevant visual stimulus.

Dehydroepiandrosterone and Dehydroepiandrosterone-Sulfate and Emotional Processing

Steroid hormones are important regulators of brain development, physiological function, and behavior. Among them, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEAS) also do modulate emotional processing and may have mood enhancement effects. This chapter reviews the studies that bear relation to DHEA and DHEAS [DHEA(S)] and brain emotional processing and behavior. A brief introduction to the mechanisms of action and variations of DHEA(S) levels throughout life has also been forward in this chapter. Higher DHEA(S) levels may reduce activity in brain regions involved in the generation of negative emotions and modulate activity in regions involved in regulatory processes. At the electrophysiological level, higher DHEA-to-cortisol and DHEAS-to-DHEA ratios were related to shorter P300 latencies and shorter P300 amplitudes during the processing of negative stimuli, suggesting less interference of negative stimuli with the task and less processing of the negative information, which in turn may suggest a protective mechanism against negative information overload. Present knowledge indicates that DHEA(S) may play a role in cortical development and plasticity, protecting against negative affect and depression, and at the same time enhancing attention and overall working memory, possibly at the cost of a reduction in emotional processing, emotional memory, and social understanding.

Crise hipercalcémica e hiperparatiroidismo primário: causa de tempestade arrítmica invulgar

Hypercalcemia is a known cause of heart rhythm disorders, however its association with ventricular arrhythmias is rare. The authors present a case of a fifty-three years old male patient with a ischemic and ethanolic dilated cardiomyopathy, and severely reduced ejection fraction, carrier of cardiac resynchronization therapy (CRT) with cardioverter defibrillator (ICD), admitted in the emergency department with an electrical storm, with multiple appropriated ICD shocks, refractory to antiarrhythmic therapy. In the etiological investigation was documented severe hypercalcemia secondary to primary hyperparathyroidism undiagnosed until then. Only after the serum calcium level reduction ventricular tachycardia was stopped.

A new mutation in thyroid hormone resistance

Introduction. Thyroid Hormone Resistance (THR) is a rare syndrome with a variable and fluctuating clinical course depending on complex genetic and molecular defects. Case report. SCPR, a caucasian female patient aged 23, was referred to outpatient endocrine department because of increased T4 levels. There was no evidence of thyroid dysfunction or goiter. Past medical history was negative with normal growth and neurophysiological development and regular menstrual cycles. There was no family history of thyroid disease. Analytical evaluation revealed T4 – 17.9 µg/dL [Reference Value (RV): 4.5-12.5], T3 – 247 ng/mL (RV: 72-170), TSH – 4.9 µU/mL (RV: 0.4-4.0), FT3 – 7.8 pg/mL (RV: 1.8-4.2), FT4 – 2.6 ng/dL (RV: 0.8-1.9), TPOAb 11 U/mL (RV: T (p.Val264Phe) with unknown significance. Discussion. Several important points are illustrated by this case. 1) thyroid function tests may fluctuate over time, only sometimes with clear evidence of THR. 2) clinical manifestations of the syndrome are multiform and the relation to thyroid hormone levels is far from clear with abnormalities of growth and neurophysiological development, infertility, obesity, psychiatric disorders or subtle symptoms suggesting thyroid dysfunction variably reported; 3) interpretation of analytical abnormalities may be difficult with thyroid dysfunction commonly misdiagnosed; 4) medical treatment is controversial; 5) More than 100 mutations have been reported and the particular complexity of thyroid hormone effects – several isoforms of the receptor, homo- or heterodimerization of the receptor with the retinoid X receptor and dominant negative effects making the interpretation of the functional significance of new mutations difficult.

A rare missense variant in RET exon 8 in a Portuguese family with atypical multiple endocrine neoplasia type 2A.

BACKGROUND AND OBJECTIVE: Multiple Endocrine Neoplasia type 2 (MEN2) is a rare genetic disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and primary hyperparathyroidism. MEN2 is an autosomal dominant syndrome caused by mutations in the RET proto-oncogene. In the vast majority of patients, the mutations are localized in exons 10, 11 and 13–15 of the RET gene. Rare variants located in exon 8 were recently identified but their clinical significance remains unclear. DESIGN AND METHODS: We studied two sisters presenting with pheochromocytoma as the first tumor. One of the sisters was diagnosed with a right pheochromocytoma at the age of 44 and at age 53 she developed an invasive left pheochromocytoma with no other endocrine neoplasia. The other sister was diagnosed with a left pheochromocytoma at age 50 and at age 64 she had a right phemochromocytoma and MTC. Neither of the two sisters presented evidence of primary hyperparathyroidism. Mutations of the RET proto-oncogene were investigated by DNA sequencing. RESULTS: We detected a germline missense variant in RET exon 8 (p.Cys531Arg) in both sisters. The p.Cys531Arg variant was not present in a third 50-year-old sister who has remained to date clinically unaffected. CONCLUSION: This is the first case showing the p.Cys531Arg variant in RET exon 8 co-segregating with family members affected by a syndrome reminiscent of MEN2A. Our results suggest that this variant has a specific genotype-phenotype correlation as it is associated with the development of pheochromocytoma before the onset of MTC.

Takotsubo Syndrome: A Pathway through the Pituitary Disease.

Takotsubo cardiomyopathy (TTC) is characterized by reversible left ventricular apical and/or midventricular hypokinesia with unknown etiology. The clinical presentation is similar to acute myocardial infarction in the absence of significant obstructive coronary artery disease. Various predisposing factors have been related to TTC, such as acute neurological illnesses, endocrine diseases, pain, and emotional stress. We present the first description of an association between TTC cardiomyopathy and panhypopituitarism. This case reinforces the connection between the hormonal and cardiovascular systems. Furthermore, it supports the importance of a comprehensive and integrated medical history in the approach of a patient with cardiac disease, towards clinical decision-making.